NO137093B - PROCEDURES FOR THE PREPARATION OF 2,4-DIAMINO-5-BENZYLPYRIMIDINES - Google Patents
PROCEDURES FOR THE PREPARATION OF 2,4-DIAMINO-5-BENZYLPYRIMIDINES Download PDFInfo
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- NO137093B NO137093B NO3624/72A NO362472A NO137093B NO 137093 B NO137093 B NO 137093B NO 3624/72 A NO3624/72 A NO 3624/72A NO 362472 A NO362472 A NO 362472A NO 137093 B NO137093 B NO 137093B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
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Description
Foreliggende oppfinnelse vedrører en fremgangsmåte til fremstilling av 2,4-diamino-5-benzylpyrimidiner. The present invention relates to a method for the production of 2,4-diamino-5-benzyl pyrimidines.
De enestående antimikrobielle egenskaper til 2,4-diamino-5-benzylpyrimidiner er velkjente (se f.eks. Falco, The outstanding antimicrobial properties of 2,4-diamino-5-benzylpyrimidines are well known (see, e.g., Falco,
E.A. et. al.: J. Am. Chem. Soc. 1951, 7_3, p. 3758). Man har nylig oppdaget at visse derivater av denne type med dialkyl- og alkoksysubstituenter i fenylringen, f.eks. 3,5-dietyl-4-metoksy-substituerte derivat, er i besittelse av spesielt gode antimalaria-og antibakterielle egenskaper. E.A. a. al.: J. Am. Chem. Soc. 1951, 7_3, p. 3758). It has recently been discovered that certain derivatives of this type with dialkyl and alkoxy substituents in the phenyl ring, e.g. 3,5-diethyl-4-methoxy-substituted derivative, has particularly good antimalarial and antibacterial properties.
Et av de store problemer i forbindelse med undersøkelsen One of the major problems in connection with the survey
av de terapeutiske muligheter for nye forbindelser i 2,4-diamino-5-benzylpyrimidin-rekken, har vært den store vanskelig- of the therapeutic possibilities for new compounds in the 2,4-diamino-5-benzylpyrimidine series, has been the great difficulty
het ved å oppnå passende substituerte utgangsmaterialer til den klassiske fremstillingsmåte, beksrevet f.eks. i britiske patenter nr. 957.797 og 1.142.654. Det anvendes her som utgangsmateriale benzaldehyd og det har vist seg meget vanskelig å oppnå de ønskede substituenter i fenylringen på enkel måte og uten større omkostninger. Dette gjelder særlig når det er tale om substituenter i 3- og 5-stillingene og når substituenten er en alkylgruppe; fremstilling av kommersielle mengder av 3,5-dialkylbenzaldehyd er nesten umulig ved konvensjonell teknikk. Når man vil fremstille 2,4-diamino-5-benzylpyrimidiner med mange forskjellige substituenter i fenylringen, er det således ønskelig å kunne anvende et annet utgangsmateriale enn benzaldehyd. het by obtaining suitable substituted starting materials for the classical production method, tarred e.g. in British Patent Nos. 957,797 and 1,142,654. The starting material used here is benzaldehyde and it has proven very difficult to obtain the desired substituents in the phenyl ring in a simple way and without major costs. This applies in particular when it comes to substituents in the 3- and 5-positions and when the substituent is an alkyl group; production of commercial quantities of 3,5-dialkylbenzaldehyde is almost impossible by conventional techniques. When one wants to prepare 2,4-diamino-5-benzylpyrimidines with many different substituents in the phenyl ring, it is thus desirable to be able to use a starting material other than benzaldehyde.
Det er tidligere kjent fra dansk patent nr. 115.847 en fremgangsmåte til fremstilling av 2,4-diamino-5-benzyl-pyrimidinderivater der 2-, 4- og 5-stillingene i fenylringen er substituert med halogenatomer eller alkyl- eller alkoksy-grupper. Fremgangsmåten består i at acetylthymin omsettes med N-bromsuccinimid til acetylbromthymin, som i nærvær av et metallhalogenid omsettes med et passende substituert benzend-derivat, hvoretter omsetningsproduktet behandles med en sterk base og deretter omsettes med et klorerings- eller bromerings-middel til det tilsvarende 2,4-diklor- eller 2,4-dibrom-5-benzylpyrimidinderivat, som omsettes med ammoniakk, hvoretter det innvunnende 2,4-diamino-5-benzylpyrimidinderivat, om ønsket, omdannes til et syreaddisjonssalt derav. Denne fremgangsmåte er som det fremgår temmelig komplisert, idet den består av ikke mindre enn 5 trinn. Da det ene utgangsmateriale er et thyminderivat omfatter fremgangsmåten nødvendigvis om-dannelse av ketogruppéné til aminogrupper hvilket skjer via hydroksyl- og halogensubstituenter. Videre omfatter fremgangsmåten nødvendigvis fjerningen av acetylgruppen fra et av nitrogenatomene i pyrimidinringen. It is previously known from Danish patent no. 115,847 a method for the production of 2,4-diamino-5-benzyl-pyrimidine derivatives in which the 2-, 4- and 5-positions in the phenyl ring are substituted with halogen atoms or alkyl or alkoxy groups. The method consists in acetylthymine being reacted with N-bromosuccinimide to acetylbromothymine, which in the presence of a metal halide is reacted with a suitably substituted benzene derivative, after which the reaction product is treated with a strong base and then reacted with a chlorinating or brominating agent to the corresponding 2 ,4-dichloro- or 2,4-dibromo-5-benzylpyrimidine derivative, which is reacted with ammonia, after which the resulting 2,4-diamino-5-benzylpyrimidine derivative is, if desired, converted into an acid addition salt thereof. As can be seen, this method is rather complicated, as it consists of no less than 5 steps. As one of the starting materials is a thymine derivative, the method necessarily includes conversion of keto groups to amino groups, which takes place via hydroxyl and halogen substituents. Furthermore, the method necessarily includes the removal of the acetyl group from one of the nitrogen atoms in the pyrimidine ring.
Det er derfor behov for en syntesevei som er forholdsvis hurtig og som kan tilveiebringe flere forbindelser relativt lett uten behov for kostbart og tidskrevende utviklings-r arbeide med' tilpasning av i og for seg kjente fremgangsmåter, således at tilstrekkelige mengder av disse materialer kan tilveiebringes i god kvalitet og på relativt'kort.tid for anvendelse ved biologisk prøving, prøving i praksis og senere til markedsføring. There is therefore a need for a synthesis route which is relatively fast and which can provide several compounds relatively easily without the need for expensive and time-consuming development work on adaptation of methods known per se, so that sufficient quantities of these materials can be provided in good quality and in a relatively short time for use in biological testing, testing in practice and later for marketing.
Det har nå vist seg at visse 2,4-diamino-5-substituerte metylpyrimidiner omsettes lett med til og med meget kraftig substituerte fenoler, skjønt den lave oppløselighet av slike forbindelser i visse tilfelle kan nødvendiggjøre anvendelsen av bestemte medier. It has now been shown that certain 2,4-diamino-5-substituted methylpyrimidines react easily with even very strongly substituted phenols, although the low solubility of such compounds may in certain cases necessitate the use of specific media.
Videre kan et av utgangspyrimidinderivatene, nemlig 2,4-diamino-5-hydroksymetylpyrimidin, som hittilhar vært meget vanskelig tilgjengelig, fremstilles med fordel ved en forbedret fremgangsmåte hvilket fremmer den industrielle an-vendelighet at hele syntesemåten. Furthermore, one of the starting pyrimidine derivatives, namely 2,4-diamino-5-hydroxymethylpyrimidine, which until now has been very difficult to obtain, can be advantageously produced by an improved method, which promotes the industrial applicability of the entire synthesis method.
Ifølge foreliggende oppfinnelse er det tilvéiebragt According to the present invention, it has been achieved
en fremgangsmåte til fremstilling" av 2,4-diamino-5-benzyl-pyrimidiner med den generelle formel: a method for the preparation" of 2,4-diamino-5-benzyl pyrimidines of the general formula:
12 12
hvor en av gruppene Q og Q betegner en 2,4-diaminopyrimidin-12 3 5-yl-metylgruppe, R , R , R og den andre Q-gruppe hver betegner et hydrogen- eller et halogenatom eller en alkyl- eller en alkoksygruppe med 1-4 og fortrinnsvis 1-3 karbonatomer, idet Q 2 kun kan betegne den ovennevnte pyrimidinylmetylgruppe, såfremt Q^" ikke betegner et hydrogenatom, og R betegner et hydrogenatom eller en alkylgruppe. where one of the groups Q and Q denotes a 2,4-diaminopyrimidin-12 3 5-yl-methyl group, R , R , R and the other Q group each denotes a hydrogen or a halogen atom or an alkyl or an alkoxy group with 1-4 and preferably 1-3 carbon atoms, Q 2 can only denote the above-mentioned pyrimidinylmethyl group, provided that Q 2 does not denote a hydrogen atom, and R denotes a hydrogen atom or an alkyl group.
Denne framgangsmåte er ifølge oppfinnelsen kjennetegnet ved at man omsetter en forbindelse med den generelle formel: hvor R <7>betegner en hydroksylgruppe, et halogenatom eller en acyloksy- eller sulfonyloksygruppe, med en substituert fenol med den generelle formel: According to the invention, this method is characterized by reacting a compound with the general formula: where R <7> denotes a hydroxyl group, a halogen atom or an acyloxy or sulfonyloxy group, with a substituted phenol of the general formula:
12 3 12 3
hvor R , R og R har den ovenfor angitte betydning, og hvor where R , R and R have the meaning given above, and where
4 5 4 5
minst en av gruppene R og R betegner et hydrogenatom og den andre betegner et hydrogen- eller et halogenatom eller en at least one of the groups R and R represents a hydrogen atom and the other represents a hydrogen or halogen atom or a
alkyl- eller en alkoksygruppe med 1-4 karbonatomer som angitt for Q, i et polart, ikke-fenolholdig oppløsningsmiddel, som er i stand til å oppløse begge reaktanter, etterfulgt, såfremt R betegner en alkylgruppe, av en alkylering av produktet med et alkyleringsmiddel med den generelle formel R Z, hvor Z betegner et reaktivt atom eller en reaktiv gruppe og R er en alkylgruppe . alkyl or an alkoxy group of 1-4 carbon atoms as indicated for Q, in a polar, non-phenolic solvent capable of dissolving both reactants, followed, if R represents an alkyl group, by alkylation of the product with an alkylating agent with the general formula R Z, where Z denotes a reactive atom or a reactive group and R is an alkyl group.
5 1 2 5 1 2
En eller flere av gruppene R , R og R kan betegne et hydrogenatom, i hvilket tilfelle man ved omsetningen oppnår forbindelser av særlig farmakologisk interesse. Særlig fore-trekkes at R 3 og R 4 hver betegner en alkylgruppe, således at sluttproduktet ved omsetningen blir et 3,5-dialkyl-4-alkoksy-substituert benzylderivat, f.eks. med en 3,5-dietylsubstituering. One or more of the groups R , R and R can denote a hydrogen atom, in which case compounds of particular pharmacological interest are obtained by the reaction. It is particularly preferred that R 3 and R 4 each denote an alkyl group, so that the end product of the reaction becomes a 3,5-dialkyl-4-alkoxy-substituted benzyl derivative, e.g. with a 3,5-diethyl substitution.
For å oppnå de høyeste utbytter og de beste resultater foretrekker man å inkorporere en som katalysator virkende sterk syre i reaksjonsmediet. Syren kan være en sterk mineral-syre, sliksom saltsyre, enten i vann som oppløsningsmiddel eller i en karboksylsyre, slik som en lavere fettsyre med opptil 4 karbonatomer, f.eks. eddiksyre, eller det kan benyttes en sulfonsyre, f.eks. p-toluen-sulfonsyre, som et alternativt polært oppløsningsmiddel. Mengden av den sure katalysator kan variere innenfor vide grenser, men mengder i området 0,2-4 N, hensiktsmessig ca. 0,3 N i vandig eller eddiksurt medium eller 3 N i p-toluensulfonsyre er tilfredsstillende til formålet. Anvendelsen"av de angitte organiske oppløsnings-midler er særlig ønskelig ved fenoler med tyngre substituenter, siden det i disse medier kan oppnås høyere konsentrasjoner ved omsetning uten utfelling av pyrimidinreaktanten. In order to achieve the highest yields and the best results, it is preferred to incorporate a strong acid acting as a catalyst into the reaction medium. The acid can be a strong mineral acid, such as hydrochloric acid, either in water as a solvent or in a carboxylic acid, such as a lower fatty acid with up to 4 carbon atoms, e.g. acetic acid, or a sulphonic acid can be used, e.g. p-toluenesulfonic acid, as an alternative polar solvent. The amount of the acidic catalyst can vary within wide limits, but amounts in the range 0.2-4 N, suitably approx. 0.3 N in aqueous or acetic acid medium or 3 N in p-toluenesulfonic acid is satisfactory for the purpose. The use of the indicated organic solvents is particularly desirable for phenols with heavier substituents, since in these media higher concentrations can be achieved by reaction without precipitation of the pyrimidine reactant.
F.eks. oppnås 2,4-diamino-5-(3,5-dietyl-4-hydroksybenzyl) pyrimidin ved omsetning av 2,6-dietylfenol med 5-hydroksymetylpyrimidin. E.g. 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine is obtained by reacting 2,6-diethylphenol with 5-hydroxymethylpyrimidine.
Den steriske innvirkning av gruppene i ortostillingene til hydroksygruppen i forbindelsene med formel II, er en viktig faktor ved den ovennevnte omsetning. Jo større disse grupper er, jo høyere tendens har hydroksygruppen til å bli tvunget ut av fenylringens plan med medfølgende fall i dens aktiverende innflytelse på ringen. Som man ville forvente, The steric influence of the groups in the ortho positions of the hydroxy group in the compounds of formula II is an important factor in the above-mentioned reaction. The larger these groups are, the higher the tendency of the hydroxy group to be forced out of the plane of the phenyl ring with a consequent decrease in its activating influence on the ring. As one would expect,
er de utbytter, som oppnås med en forbindelse med den generelle are the dividends, which are obtained with a connection with the general
formel II, som har tert.-butylgrupper i orto-stillingene til hydroksygruppen, vesentlig lavere enn de som oppnås med mindre voluminøse substituenter, på grunn av den store steriske virkning av disse grupper. formula II, which have tert.-butyl groups in the ortho-positions of the hydroxy group, significantly lower than those obtained with less bulky substituents, due to the large steric effect of these groups.
Når kondensasjonsreaksjonen mellom pyrimidin- og fenol-reaktantene finner sted i et medium av en karboksylsyre eller en organisk sulfonsyre, dannes det ved anvendelse av en 2,4-diamino-5-hydroksymetylpyrimidin som utgangsmateriale, et hittil ukjent mellomprodukt med den generelle formel: When the condensation reaction between the pyrimidine and phenol reactants takes place in a medium of a carboxylic acid or an organic sulphonic acid, using a 2,4-diamino-5-hydroxymethylpyrimidine as starting material, a hitherto unknown intermediate with the general formula is formed:
hvor R 7 er en acyloksygruppe eller en sulfonyloksygruppe. Forbindelsene med den generelle formel III, f.eks. acetyl-mellomproduktet, er funnet og isolert og det har vist seg at de omsettes med fenoler med den generelle formel II til forbindelser med den generelle formel I. Slike forbindelser med den generelle formel III kan også fremstilles fra 2,4-diamino-5-brometylpyrimidin ved omsetning med det tilsvarende natriumsalt, f.eks. natriumacetat. where R 7 is an acyloxy group or a sulfonyloxy group. The compounds of the general formula III, e.g. the acetyl intermediate, has been found and isolated and it has been shown that they react with phenols of the general formula II to compounds of the general formula I. Such compounds of the general formula III can also be prepared from 2,4-diamino-5- bromethylpyrimidine by reaction with the corresponding sodium salt, e.g. sodium acetate.
Om ønsket kan 2'- eller 4'-hydroksygruppen i forbindelsen med den generelle formel I, omdannes til en alkoksygruppe ved omsetning av forbindelsen med et alkyleringsmiddel If desired, the 2'- or 4'-hydroxy group in the compound of the general formula I can be converted into an alkoxy group by reacting the compound with an alkylating agent
6 6 6 6
med den generelle formel R Z, hvor R er en alkylgruppe og Z with the general formula R Z, where R is an alkyl group and Z
er et reaktivt atom, f.eks. et halogenatom, eller en reaktiv gruppe, f.eks. en sulfatgruppe. is a reactive atom, e.g. a halogen atom, or a reactive group, e.g. a sulfate group.
Under praktiske betingelser betegner R vanligvis en alkylgruppe med opptil 12 karbonatomer, fortrinnsvis 1-8 og spesielt 1-4 karbonatomer. Under practical conditions, R usually denotes an alkyl group of up to 12 carbon atoms, preferably 1-8 and especially 1-4 carbon atoms.
Omsetningen av hydroksylgruppen med forbindelsen med formel R Z kan oppnås i nærvær av en base av tilstrekkelig styrke for dannelse av et fenatanion, f.eks. en base slik som natriumhydroksyd eller kalium-tert.-butoksyd. The reaction of the hydroxyl group with the compound of formula R Z can be achieved in the presence of a base of sufficient strength to form a phenanion, e.g. a base such as sodium hydroxide or potassium tert-butoxide.
Ved foreliggende fremgangsmåte kan foruten kjente forbindelser med den generelle formel I fremstilles hittil ukjente forbindelser med den generelle formel: With the present method, in addition to known compounds with the general formula I, hitherto unknown compounds with the general formula can be prepared:
hvori substituentene har den ovenfor angitte betydning, idet in which the substituents have the meaning indicated above, as
12 12
dog minst en av substituentene R og R skal betegne en substituent som ikke er et hydrogenatom såfremt Q betegner en 2,4-diaminopyrimidin-5-ylmetylgruppe og minst en av however, at least one of the substituents R and R must denote a substituent that is not a hydrogen atom provided that Q denotes a 2,4-diaminopyrimidin-5-ylmethyl group and at least one of
3 2 3 2
substituentene R og Q betegnet en alkyl- eller en alkoksygruppe. Foruten forbindelsene med formel IV tilveiebringes ved foreliggende fremgangsmåte også ytterligere mellom-produkter med den generelle formel I, hvor R er et hydrogenatom, og som kun har 3,5-dialkylsubstitusjon på 4-hydroksy-fenylgruppen, hvor hver alkylgruppe kan betegne en metyl-, en etyl- eller propylgruppe, f.eks. 3,5- dimetyl-, -dietyl-eller-diisopropylsubstituerende forbindelser. the substituents R and Q denoted an alkyl or an alkoxy group. In addition to the compounds of formula IV, the present process also provides further intermediates of the general formula I, where R is a hydrogen atom, and which only has 3,5-dialkyl substitution on the 4-hydroxy-phenyl group, where each alkyl group can denote a methyl- , an ethyl or propyl group, e.g. 3,5-dimethyl-, -diethyl- or -diisopropyl-substituted compounds.
Fenolene med formel II kan hensiktsmessig tilveiebringes ved i og for seg kjente generelle fremgangsmåter, The phenols of formula II can conveniently be provided by general methods known per se,
slik som Friedel-Crafts kondensasjon med fenoler eller dia-zotering og hydrolyse av de tilsvarende anilinderivater. such as Friedel-Crafts condensation with phenols or diazotization and hydrolysis of the corresponding aniline derivatives.
Hittil har man fremstilt den ifølge oppfinnelsen som utgangsmateriale benyttede 2,4-diamino-5-hydroksymetylpyrimidin ved en to-trinns omsetning, som besto av en katalytisk, hydro-lytisk hydrogenering av 2,4-diamino-5-cyanpyrimidin til 2,4-diamino-5-formylpyrimidin, etterfulgt av reduksjon med natrium-borhydrid til dannelse av 5-hydroksypyrimidinforbindelsen (kfr. Journal of Medicinal Chemistry, 1968, 11, p. 1238). Denne fremgangsmåte ga imidlertid temmelig skuffende utbytter. Until now, the 2,4-diamino-5-hydroxymethylpyrimidine used as starting material according to the invention has been produced by a two-stage reaction, which consisted of a catalytic, hydrolytic hydrogenation of 2,4-diamino-5-cyanopyrimidine to 2,4 -diamino-5-formylpyrimidine, followed by reduction with sodium borohydride to form the 5-hydroxypyrimidine compound (cf. Journal of Medicinal Chemistry, 1968, 11, p. 1238). However, this approach gave rather disappointing results.
Det har nå vist seg at den hydrolytiske hydrogenering av 2,4-diamino-5-cyanpyrimidin til 2,4-diamino-5-formyl-pyrimidin med fordel kan utføres med Raney-nikkel eller med nikkel-aluminiumlegering som katalysator i nærvær av en syre. It has now been shown that the hydrolytic hydrogenation of 2,4-diamino-5-cyanopyrimidine to 2,4-diamino-5-formyl-pyrimidine can be advantageously carried out with Raney nickel or with nickel-aluminum alloy as catalyst in the presence of a acid.
I forbindelse med dette bør det bemerkes at maursyre fore-trekkes på grunn av de herved oppnådde meget høye utbytter. Det kan imidlertid også benyttes etanolisk saltsyre. En betraktelig forbedring i utbytte oppnås, og produktet er spesielt velegnet til videre opparbeidelse til 2,4-diamino-5-hydroksymetylpyrimidin ved videre selektiv reduksjon, f.eks. In connection with this, it should be noted that formic acid is preferred because of the very high yields achieved thereby. However, ethanolic hydrochloric acid can also be used. A considerable improvement in yield is achieved, and the product is particularly suitable for further processing to 2,4-diamino-5-hydroxymethylpyrimidine by further selective reduction, e.g.
med borhydrid, som beskrevet i litteraturen. with borohydride, as described in the literature.
Forbindelser med generell formel V, hvor R er et brom-atom, kan fremstilles ved bromering av den tilsvarende hydroksy-forbindelse med formel V. Compounds of general formula V, where R is a bromine atom, can be prepared by bromination of the corresponding hydroxy compound of formula V.
Fremgangsmåten ifølge oppfinnelsen belyses nærmere The method according to the invention is explained in more detail
under henvisning til følgende eksempler. with reference to the following examples.
Eksempel 1. Example 1.
1 g 2,4-diamino-5-cyanpyrimidin (fremstilt som beskrevet av Huber, W.: Journal of the American Chemical Society, 1 g of 2,4-diamino-5-cyanopyrimidine (prepared as described by Huber, W.: Journal of the American Chemical Society,
1943, 65, p. 2223) oppløses i 15 ml 75% maursyre og det tilsettes 1 g 50:50 Ni-Al legering. Suspensjonen kokes under til-bakeløp i 1 time, filtreres i varm tilstand og inndampes deretter til tørrhet i en rotasjonsinndamper. Resten fortynnes med vann og gjøres basisk med nåtriumhydroksydoppløsning. Bunn-fallet frafiltreres og renses ved omkrystallisering av 100 ml 1943, 65, p. 2223) is dissolved in 15 ml of 75% formic acid and 1 g of 50:50 Ni-Al alloy is added. The suspension is refluxed for 1 hour, filtered while hot and then evaporated to dryness in a rotary evaporator. The residue is diluted with water and made basic with sodium hydroxide solution. The precipitate is filtered off and purified by recrystallization of 100 ml
vann eller ved å oppløse det i 50% eddiksyre og nøytralisere med base (f.eks. natriumhydroksyd- eller ammoniumhydroksydoppløsninger). Produktet oppnås som farveløse nåler fra vann i smp. 273-275°C (dekomp.). Utbytte: 66%. water or by dissolving it in 50% acetic acid and neutralizing with a base (e.g. sodium hydroxide or ammonium hydroxide solutions). The product is obtained as colorless needles from water at m.p. 273-275°C (decomp.). Yield: 66%.
Resultatene fra grunnstoffanalyse, ultrafiolett spektro-skop!, infrarød spektroskopi, massespektroskopi, tynnsjiktskromatografi og gassfasekrbmatografi viser alle at produktet er 2,4-diamino-5-formylpyrimidin. The results from elemental analysis, ultraviolet spectroscopy, infrared spectroscopy, mass spectroscopy, thin layer chromatography and gas phase chromatography all show that the product is 2,4-diamino-5-formylpyrimidine.
2,4-diam ino- 5- hydroksymetylpyrimidin. 2,4-diamino-5-hydroxymethylpyrimidine.
Forbindelsene oppnås utfra den ovenfor fremstilte 2,4-diamino-5-formylpyrimidin ved reduksjon ved de i Journal of Medicinal Chemistry, 1968, 11, p.1238 beskrevne betingelser. 2, 4- diamino- 5-( 3, 5- dietyl- 4- hydroksybenzyl) pyrimidin. The compounds are obtained from the 2,4-diamino-5-formylpyrimidine prepared above by reduction under the conditions described in Journal of Medicinal Chemistry, 1968, 11, p.1238. 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine.
1,4 g (0,01 mol) 2,4-diamino-5-hydroksymetylpyrimidin og 1,6 g (0,01 mol) 2,6-dietylfenol i 100 ml iseddiksyre inneholdende 3 ml konsentrert saltsyre, oppvarmes på et dampbad. 1.4 g (0.01 mol) of 2,4-diamino-5-hydroxymethylpyrimidine and 1.6 g (0.01 mol) of 2,6-diethylphenol in 100 ml of glacial acetic acid containing 3 ml of concentrated hydrochloric acid are heated on a steam bath.
Det først dannende bunnfall går langsomt i oppløsning. Etter The initially forming precipitate slowly dissolves. After
5 timer avkjøles.reaksjonsblandingen og inndampes til tørrhet i en rotasjonsinndamper. Resten behandles med 50 ml aceton og ved rivning oppnås et granulært fast stoff. After 5 hours, the reaction mixture is cooled and evaporated to dryness in a rotary evaporator. The residue is treated with 50 ml of acetone and a granular solid is obtained by trituration.
Det faste stoff frafiltreres og omkrystalliseres fra vann hvorved produktet oppnås som hydroklorid med smp. 277-279°C. The solid substance is filtered off and recrystallized from water whereby the product is obtained as hydrochloride with m.p. 277-279°C.
Alternativt kan det urene faste stoff eller hydrokloridet oppløses i varmt vann og nøytraliseres med en natrium-hydrogenkarbonatoppløsning hvorved man oppnår den frie base. Ved omkrystallisering fra vandig etanol oppnås 2,4-diamino-5-(3,5-dietyl-4-hydroksybenzyl)pyrimidin som farveløse nåler med smp. 204-205°C. Utbytte: 66%. Alternatively, the impure solid or the hydrochloride can be dissolved in hot water and neutralized with a sodium bicarbonate solution, whereby the free base is obtained. By recrystallization from aqueous ethanol, 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine is obtained as colorless needles with m.p. 204-205°C. Yield: 66%.
Eksempel 2. Example 2.
1,4 g 2,4-diamino-5-hydroksymetylpyrimidin, fremstilt som i eksempel 1, og 1,6 g 2,6-dietylfenol i 10 g p-toluensulfonsyre inneholdende 3 ml konsentrert saltsyre, oppvarmes på et dampbad i 6 timer.. Oppløsningen avkjøles og fortynnes med eter og eteren fradekanteres. Resten behandles med en oppløsning av natriumhydrogenkarbonat og det faste stoff frafiltreres. Ved omkrystallisering av vandig etanol oppnås 2,4-diamino-5-(3,5-dietyl-4-hydroksybenzyl)pyrimidin i form av farveløse nåler med smp. 200-202°C.. 1.4 g of 2,4-diamino-5-hydroxymethylpyrimidine, prepared as in example 1, and 1.6 g of 2,6-diethylphenol in 10 g of p-toluenesulfonic acid containing 3 ml of concentrated hydrochloric acid are heated on a steam bath for 6 hours. The solution is cooled and diluted with ether and the ether is decanted off. The residue is treated with a solution of sodium bicarbonate and the solid is filtered off. By recrystallization from aqueous ethanol, 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine is obtained in the form of colorless needles with m.p. 200-202°C..
Eksempel 3. Example 3.
Fremgangsmåten fra eksempel 1 gjentas med 2,6-diiso-propylfenol som reaktant. Man oppnår 2,4-diamino-5-(3,5-diisopropyl-4-hydroksybenzyl)pyrimidin i et et utbytte på 40%, den frie base har et smeltepunkt på 244-246°C. The procedure from example 1 is repeated with 2,6-diisopropylphenol as reactant. 2,4-diamino-5-(3,5-diisopropyl-4-hydroxybenzyl)pyrimidine is obtained in a yield of 40%, the free base has a melting point of 244-246°C.
Eksempel 4. Example 4.
De ved de i foregående eksempler beskrevne fremgangsmåter fremstilte 4-hydroksybenzylpyrimidiner omdannes til de tilsvarende 4-metoksyderivater ved nedenstående fremgangsmåte: 0,005 mol av den aktuelle 5-(4-hydroksybenzyl)pyrimidin oppløses i 10 ml tørr dimetylsulfoksyd og det tilsettes litt over 0,005 mol av et natriumalkoksyd. Deretter tilsettes litt over 0,005 mol metyliodid og den tilstoppede reaksjonskolbe henstilles i mørke i 3-4 døgn. The 4-hydroxybenzylpyrimidines produced by the methods described in the previous examples are converted into the corresponding 4-methoxy derivatives by the following method: 0.005 mol of the relevant 5-(4-hydroxybenzyl)pyrimidine is dissolved in 10 ml of dry dimethylsulfoxide and just over 0.005 mol of a sodium alkoxide. A little over 0.005 mol of methyl iodide is then added and the stoppered reaction flask is left in the dark for 3-4 days.
Oppløsningen uthelles deretter i vann og produktet fjernes ved filtrering eller ved ekstraksjon i etylacetat og inndampning. Det omkrystalliseres fra vandig etanol. The solution is then poured into water and the product is removed by filtration or by extraction into ethyl acetate and evaporation. It is recrystallized from aqueous ethanol.
Det viste seg at man oppnådde tilfredsstillende metylering for.begge hydroksybenzylpyrimidiner, hvorved det oppnås 2,4-diamino-5-(3,5- dietyl-4-metoksy)pyrimidin (smp. 153"C) og 2,4-diamino-5-(3,5-diisopropyl-4-metoksy)pyrimidin (smp. 205-207°C). It turned out that satisfactory methylation was achieved for both hydroxybenzylpyrimidines, whereby 2,4-diamino-5-(3,5-diethyl-4-methoxy)pyrimidine (m.p. 153°C) and 2,4-diamino- 5-(3,5-diisopropyl-4-methoxy)pyrimidine (m.p. 205-207°C).
Eksempel 5. Example 5.
1,4 g 2,4-diamino-5-hydroksymetylpyrimidin, fremstilt 1.4 g of 2,4-diamino-5-hydroxymethylpyrimidine, prepd
som i eksempel 1, og 1,1 g 2,6-dimetylfenol kokes under til-bakeløp i 30 ml vann inneholdende 1 ml konsentrert saltsyre og litt aceton for å lette oppløsningen av fenolen. Etter 5 as in example 1, and 1.1 g of 2,6-dimethylphenol is refluxed in 30 ml of water containing 1 ml of concentrated hydrochloric acid and a little acetone to facilitate the dissolution of the phenol. After 5
timers koking under tilbakeløp, avkjøles reaksjonsblandingen og produktet frafiltreres. Ved omkrystallisering fra vann oppnås produktet som hydroklorid med smp. 280°C (langsom dekomp.). Den frie base oppnås på vanlig måte med smp. 242-244°C. hours of boiling under reflux, the reaction mixture is cooled and the product is filtered off. By recrystallization from water, the product is obtained as hydrochloride with m.p. 280°C (slow decomp.). The free base is obtained in the usual way with m.p. 242-244°C.
Eksempel 6. Example 6.
Fremgangsmåten fra eksempel 2 gjentas med 2,6-dimetylfenol, 2,3,5,6-tetrametylfenol og 2,6-dimetoksyfenol, hvorved man oppnår de tilsvarende substituerte 2,4-diamino-5-benzyl-pyrimidiner, dvs. 2,4-diamino-5-(3,5,dimetyl-4-hydroksybenzyl) pyrimidin (smp. 280°C (dekomp.)), 2,4-diamino-5-(2,3,5,6-tetrametyl-4-hydroksybenzyl)pyrimidin (smp. 33 0°C) og en blanding av 2,4-diamino-5-(3,5-dimetoksy-4-hydroksybenzyl) pyrimidin (smp. 265-270°C (dekomp.)) og 2,4-diamino-5-(2,4-dimetoksy-3-hydroksybenzyl)pyrimidin (smp. 246-248°C). The procedure from example 2 is repeated with 2,6-dimethylphenol, 2,3,5,6-tetramethylphenol and 2,6-dimethoxyphenol, whereby the corresponding substituted 2,4-diamino-5-benzyl-pyrimidines are obtained, i.e. 2, 4-diamino-5-(3,5,dimethyl-4-hydroxybenzyl)pyrimidine (m.p. 280°C (decomp.)), 2,4-diamino-5-(2,3,5,6-tetramethyl-4 -hydroxybenzyl)pyrimidine (m.p. 33 0°C) and a mixture of 2,4-diamino-5-(3,5-dimethoxy-4-hydroxybenzyl)pyrimidine (m.p. 265-270°C (decomp.)) and 2,4-diamino-5-(2,4-dimethoxy-3-hydroxybenzyl)pyrimidine (m.p. 246-248°C).
Eksempel 7. Example 7.
Fremgangsmåten fra eksempel 1 gjentas idet 2,6-dietylfenol erstattes med 2,6-dimetylfenol. The procedure from example 1 is repeated, replacing 2,6-diethylphenol with 2,6-dimethylphenol.
Man oppnår 2,4-diamino-5-(3,5-dimetyl-4-hydroksybenzyl) pyrimidin (smp. 280°C (dekomp.)) i et utbytte på 58%. Hydrokloridet smelter ved 280°C under langsom dekomponering. 2,4-diamino-5-(3,5-dimethyl-4-hydroxybenzyl)pyrimidine (m.p. 280°C (decomp.)) is obtained in a yield of 58%. The hydrochloride melts at 280°C during slow decomposition.
Eksempel 8. Example 8.
Fremgangsmåten fra eksempel 1 gjentas med fenol isteden for 2,6-dietylfenol. 2,4-diamino-5-(4-hydroksybenzyl)pyrimidin (smp. 303-306°C) isoleres i tilfredsstillende utbytte. The procedure from example 1 is repeated with phenol instead of 2,6-diethylphenol. 2,4-diamino-5-(4-hydroxybenzyl)pyrimidine (m.p. 303-306°C) is isolated in satisfactory yield.
Eksempel 9. Example 9.
Fremgangsmåten fra eksempel 1 gjentas med 2,4-dimetylfenol isteden for 2,6-dietylfenol. 2,4-diamino-5-(2-hydroksy-3,5-dimetylbenzyl)pyrimidin oppnås i tilfredsstillende utbytte. Smeltepunkt av hydrokloridet er 279-281°C (dekomp.). The procedure from example 1 is repeated with 2,4-dimethylphenol instead of 2,6-diethylphenol. 2,4-diamino-5-(2-hydroxy-3,5-dimethylbenzyl)pyrimidine is obtained in satisfactory yield. Melting point of the hydrochloride is 279-281°C (decomp.).
Eksempel 10. Example 10.
Fremgangsmåten fra eksempel 1 gjentas med 2,3,5,6-tetrametylfenol isteden for 2,6-dietylfenol. 2,4-diamino-5-(2,3,5,6-tetrametyl-4-hydroksybenzyl)pyrimidin oppnås i et utbytte på 60% (smp. av hydrokloridet er større enn 330°C). The procedure from example 1 is repeated with 2,3,5,6-tetramethylphenol instead of 2,6-diethylphenol. 2,4-diamino-5-(2,3,5,6-tetramethyl-4-hydroxybenzyl)pyrimidine is obtained in a yield of 60% (m.p. of the hydrochloride is greater than 330°C).
Eksempel 11. Example 11.
Fremgangsmåten fra eksempel 1 gjentas med 2,6-dimetoksyfenol isteden for 2,6-dietylfenol. Det oppnås et godt utbytte av en blanding av 2,4-diamino-5-(3,5-dimetoksy-4-hydroksybenzyl)pyrimidin og 2,4-diamino-5-(2,4-dimetoksy-3-hydroksybenzyl)pyrimidin. Blandingens komponenter kan adskilles ved fraksjonert krystallisering. Den sistnevnte forbindelse (den frie base) smelter ved 246-248°C. The procedure from example 1 is repeated with 2,6-dimethoxyphenol instead of 2,6-diethylphenol. A good yield is obtained from a mixture of 2,4-diamino-5-(3,5-dimethoxy-4-hydroxybenzyl)pyrimidine and 2,4-diamino-5-(2,4-dimethoxy-3-hydroxybenzyl)pyrimidine . The components of the mixture can be separated by fractional crystallization. The latter compound (the free base) melts at 246-248°C.
Eksempel 12. Example 12.
Fremgangsmåten fra eksempel 1 gjentas med 2-metoksyfenol isteden for 2,6-dietylfenol. 2,4-diamino-5-(3-metoksy-4-hydroksybenzyl)pyrimidin isoleres som hydrokloridsaltet, The procedure from example 1 is repeated with 2-methoxyphenol instead of 2,6-diethylphenol. 2,4-diamino-5-(3-methoxy-4-hydroxybenzyl)pyrimidine is isolated as the hydrochloride salt,
smp. 263-265°C. m.p. 263-265°C.
Eksempel 13. Example 13.
Den i eksempel 4 beskrevne fremgangsmåte til metylering gjentas med de i eksempler 11 og 12 angitt produkter, hvorved man oppnår de tilsvarende 2,4-diamino-5-benzylpyrimidiner med nedenstående substitusjoner på benzylringen: The method for methylation described in example 4 is repeated with the products indicated in examples 11 and 12, whereby the corresponding 2,4-diamino-5-benzylpyrimidines are obtained with the following substitutions on the benzyl ring:
Eksempel 14. Example 14.
Den i eksempel 4 beskrevne fremgangsmåte til metylering gjentas med de i eksemplene 5, 6, 8, 9, 11 og 12 angitte produkter, hvorved man oppnår de tilsvarende 2,4-diamino-5-benzylpyrimidiner med nedenstående substitusjoner på benzylringen: The method for methylation described in example 4 is repeated with the products indicated in examples 5, 6, 8, 9, 11 and 12, whereby the corresponding 2,4-diamino-5-benzylpyrimidines with the following substitutions on the benzyl ring are obtained:
Eksempel 15. Example 15.
De i eksemplene 1-3 og 5-12 oppnådde forbindelser etyleres med etyliodid i det vesentlige som beskrevet i eksempel 4, hvorved man f.eks. oppnår 2,4-diamino-5-(2,3,5,6-tetrametyl-4- etoksybenzyl)pyrimidin (smp. 276-278°C). The compounds obtained in examples 1-3 and 5-12 are ethylated with ethyl iodide essentially as described in example 4, whereby e.g. obtains 2,4-diamino-5-(2,3,5,6-tetramethyl-4-ethoxybenzyl)pyrimidine (m.p. 276-278°C).
Eksempel 16. Example 16.
Til 3 g 2,4-diamino-5-brometylpyrimidinhydrobromid i To 3 g of 2,4-diamino-5-bromomethylpyrimidine hydrobromide i
50 ml eddiksyre tilsettes 3,2 g vannfri natriumacetat. Blandingen oppvarmes i 15 minutter på et dampbad, filtreres 50 ml of acetic acid is added to 3.2 g of anhydrous sodium acetate. The mixture is heated for 15 minutes on a steam bath, filtered
og avkjøles. and cool.
Det hvite faste stoff frafiltereres og omkrystalliseres fra eddiksyre. Utbytte: 3,2 g, smp. 292-295°C (dekomp.). The white solid is filtered off and recrystallized from acetic acid. Yield: 3.2 g, m.p. 292-295°C (decomp.).
Tynnsjiktskromatografi viser produktet som en enkelt flekk med samme Rf-verdi som det mellomprodukt som dannes in situ fra 2,4-diamino-5-(hydroksymetyl)pyrimidin. Denne forbindelse er vist å være 2,4-diamino-5-(acetoksymetyl)pyrimidin. Ved anvendelse av de i eksempel 1 beskrevne eksperimentelle betingelser, ble acetoksymetylderivatet omdannet til 2,4-diamino-5-(3,5-dietyl-4-hydroksybenzyl)pyrimidin (smp. 204-205°C) . Thin layer chromatography shows the product as a single spot with the same Rf value as the intermediate formed in situ from 2,4-diamino-5-(hydroxymethyl)pyrimidine. This compound is shown to be 2,4-diamino-5-(acetoxymethyl)pyrimidine. Using the experimental conditions described in example 1, the acetoxymethyl derivative was converted to 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine (m.p. 204-205°C).
Eksempel 17 . Example 17.
1,4 g 2,4-diamino-5-hydroksymetylpyrimidin oppløses 1.4 g of 2,4-diamino-5-hydroxymethylpyrimidine are dissolved
i 10 g p-toluensulfonsyre ved 120°C og det tilsettes 3 ml konsentrert saltsyre. Det første utfelte produkt går atter i oppløsning ved omrøring ved 120°C. Reaksjonsblandingen om-røres i 2 timer og uthelles deretter i 50 ml aceton. Farve-løse plateformede krystaller av 2,4-diamino-5-(p-toluensulfonyl-oksymetyl)pyrimidin frafiltreres (smp. 176-178°C). in 10 g of p-toluenesulfonic acid at 120°C and 3 ml of concentrated hydrochloric acid is added. The first precipitated product dissolves again when stirred at 120°C. The reaction mixture is stirred for 2 hours and then poured into 50 ml of acetone. Colorless plate-shaped crystals of 2,4-diamino-5-(p-toluenesulfonyl-oxymethyl)pyrimidine are filtered off (m.p. 176-178°C).
Denne forbindelse omsettes deretter med 2,6-dietylfenol som beskrevet i eksempel 1, hvorved man oppnår 2,4-diamino-5- (3,5-dietyl-4-hydroksybenzyl)pyrimidin med smp. 204-205°C. This compound is then reacted with 2,6-diethylphenol as described in example 1, whereby 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine is obtained with m.p. 204-205°C.
Eksempel 18. Example 18.
2,4-diamino-5-brometylpyrimidin omsettes med 2,6- 2,4-diamino-5-bromomethylpyrimidine is reacted with 2,6-
dietylfenol ved de 1 eksempel 1 beskrevne eksperimentelle betingelser. 2,4-diamino-5-(3,5-dietyl-4-hydroksybenzyl) diethylphenol under the experimental conditions described in Example 1. 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)
pyrimidin oppnås i et utbytte på ca. 65%. pyrimidine is obtained in a yield of approx. 65%.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO771463A NO147715C (en) | 1971-10-12 | 1977-04-27 | 2,4-DIAMINOPYRIMIDINE COMPOUND FOR USE IN THE PREPARATION OF DIAMINOBENZYLPYRIMIDINES |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4749271A GB1413471A (en) | 1971-10-12 | 1971-10-12 | 2,4-diamino-5-benzylpyrimidines and a process for their preparation |
| GB5751271 | 1971-12-10 |
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| NO137093B true NO137093B (en) | 1977-09-19 |
| NO137093C NO137093C (en) | 1977-12-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO3624/72A NO137093C (en) | 1971-10-12 | 1972-10-10 | PROCEDURES FOR THE PREPARATION OF 2,4-DIAMINO-5-BENZYLPYRIMIDINES |
Country Status (21)
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| US (1) | US4116958A (en) |
| JP (1) | JPS5328434B2 (en) |
| AR (1) | AR197006A1 (en) |
| AU (1) | AU474788B2 (en) |
| BE (1) | BE789904A (en) |
| CA (1) | CA997763A (en) |
| CH (1) | CH593267A5 (en) |
| DD (1) | DD102696A5 (en) |
| DE (2) | DE2264413A1 (en) |
| DK (1) | DK132795C (en) |
| ES (1) | ES407479A1 (en) |
| FI (2) | FI56176C (en) |
| FR (1) | FR2157843B1 (en) |
| GB (1) | GB1413471A (en) |
| IE (1) | IE37072B1 (en) |
| IL (2) | IL47450A (en) |
| NL (1) | NL7213685A (en) |
| NO (1) | NO137093C (en) |
| PL (1) | PL78480B1 (en) |
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| US4255574A (en) * | 1973-02-26 | 1981-03-10 | Hoffmann-La Roche Inc. | Process for preparing 2,4-diamino-pyrimidines |
| CH592066A5 (en) * | 1973-02-26 | 1977-10-14 | Hoffmann La Roche | |
| JPS54154775A (en) * | 1978-05-24 | 1979-12-06 | Wellcome Found | Benzylpyrimidine derivative |
| IT1138146B (en) * | 1981-08-11 | 1986-09-17 | Proter Spa | PROCESS FOR THE PRODUCTION OF 2,4-DIAMINE- (3,5-DIMETHOXY-4-METOS SIETOXY-BENZYL) -PYRIMIDINE |
| JPS6175513A (en) * | 1985-07-01 | 1986-04-17 | Hitachi Ltd | Manufacture of silicon crystal film |
| UA111630C2 (en) | 2011-10-06 | 2016-05-25 | Сіс Рісорсез Лтд. | BURNING SYSTEM |
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| DE1204678B (en) * | 1958-04-18 | 1965-11-11 | Wellcome Found | Process for the preparation of 2,4-diamino-5-benzylpyrimidines which are bromine-substituted in the 5'- or 6'-position |
| GB920412A (en) * | 1958-04-18 | 1963-03-06 | Wellcome Found | Pyrimidine derivatives and the manufacture thereof |
| DE1303727B (en) * | 1959-09-03 | 1976-02-05 | Ausscheidung aus: 14 45 176 The Wellcome Foundation Ltd., London | Alpha-arylidene-substituted propioni-iriles |
| GB1142654A (en) * | 1965-10-28 | 1969-02-12 | Wellcome Found | Cyano-acetals and their use in benzylpyrimidine synthesis |
| GB1128234A (en) * | 1966-02-19 | 1968-09-25 | Wellcome Found | 5-benzylpyrimidine derivatives and process for the preparation thereof |
| BE710100A (en) * | 1967-02-02 | 1968-07-30 | ||
| GB1247347A (en) * | 1968-01-19 | 1971-09-22 | Burroughs Wellcome Co | Pyrimidine derivatives, the preparation thereof and compositions containing the same |
| DK120706B (en) * | 1969-01-27 | 1971-07-05 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -pyrimidine. |
| US3819629A (en) * | 1970-02-10 | 1974-06-25 | Burroughs Wellcome Co | Method for preparing 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine |
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1971
- 1971-10-12 GB GB4749271A patent/GB1413471A/en not_active Expired
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1972
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- 1972-10-10 DE DE2249532A patent/DE2249532A1/en active Granted
- 1972-10-10 AR AR244552A patent/AR197006A1/en active
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- 1972-10-10 IL IL47450A patent/IL47450A/en unknown
- 1972-10-10 SE SE7213032A patent/SE405119B/en unknown
- 1972-10-10 NO NO3624/72A patent/NO137093C/en unknown
- 1972-10-10 FR FR7235802A patent/FR2157843B1/fr not_active Expired
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1975
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Also Published As
| Publication number | Publication date |
|---|---|
| JPS5328434B2 (en) | 1978-08-15 |
| DE2249532A1 (en) | 1973-04-26 |
| SE7506083L (en) | 1975-05-28 |
| CH593267A5 (en) | 1977-11-30 |
| DD102696A5 (en) | 1973-12-20 |
| FR2157843A1 (en) | 1973-06-08 |
| DE2264413C2 (en) | 1987-05-21 |
| IE37072B1 (en) | 1977-04-27 |
| IL40533A (en) | 1976-03-31 |
| GB1413471A (en) | 1975-11-12 |
| JPS4844270A (en) | 1973-06-26 |
| DE2249532C2 (en) | 1987-06-19 |
| SE405119B (en) | 1978-11-20 |
| NL7213685A (en) | 1973-04-16 |
| DE2264413A1 (en) | 1974-04-18 |
| IL40533A0 (en) | 1972-12-29 |
| PL78480B1 (en) | 1975-06-30 |
| AU474788B2 (en) | 1976-08-05 |
| IE37072L (en) | 1973-04-12 |
| AR197006A1 (en) | 1974-03-08 |
| SE413506B (en) | 1980-06-02 |
| DK132795C (en) | 1976-07-12 |
| FI800174A7 (en) | 1981-01-01 |
| US4116958A (en) | 1978-09-26 |
| AU4766772A (en) | 1974-04-26 |
| FI56176C (en) | 1979-12-10 |
| FR2157843B1 (en) | 1977-01-14 |
| IL47450A (en) | 1976-03-31 |
| FI56176B (en) | 1979-08-31 |
| CA997763A (en) | 1976-09-28 |
| BE789904A (en) | 1973-04-10 |
| ES407479A1 (en) | 1976-02-01 |
| NO137093C (en) | 1977-12-28 |
| ZM16472A1 (en) | 1974-04-22 |
| DK132795B (en) | 1976-02-09 |
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